The present invention relates to novel conjugated forms of pharmacologically active agents, and methods for the preparation and use thereof. In a particular aspect of the invention, methods are provided for treating a pathological condition with a protected form of a pharmacologically active agent, thereby reducing the occurrence of side-effects caused thereby.
Despite the advent of modern pharmaceutical technology, many drugs still possess untoward toxicities which often limit the therapeutic potential thereof. For example, although non-steroid anti-inflammatory drugs (NSAIDs) are a class of compounds which are widely used for the treatment of inflammation, pain and fever, NSAIDs (e.g., naproxen, aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, a side-effect that remains the major limitation to the use of NSAIDs (see, for example, J. L. Wallace, in Gastroenterol. 112:1000-1016 (1997); A. H. Soll et al., in Ann Intern Med. 114:307-319 (1991); and J. Bjarnason et al., in Gastroenterol. 104:1832-1847 (1993)).
There are two major ulcerogenic effects of NSAIDs: (1) topical irritant effects on the epithelium of the gastrointestinal tract and (2) suppression of gastrointestinal prostaglandin synthesis. In recent years, numerous strategies have been attempted to design and develop new NSAIDs that reduce the damage to the gastrointestinal tract. These efforts, however, have largely been unsuccessful. For example, enteric coating or slow-release formulations designed to reduce the topical irritant properties of NSAIDs have been shown to be ineffective in terms of reducing the incidence of clinically significant side effects, including perforation and bleeding (see, for example, D. Y. Graham et al., in Clin. Pharmacol. Ther. 38:65-70 (1985); and J. L. Carson, et al., in Arch. Intern. Med., 147:1054-1059 (1987)).
As another strategy to address the potential for NSAIDs to produce clinically significant side effects, Medford et al. (see, for example, PCT Publication No. WO 95/30415 and U.S. Pat. No. 5,807,884) have proposed preparation of drug derivatives of dithiocarbomates having the structure:
Axe2x80x94Sxe2x80x94C(S)xe2x80x94B,
wherein B represents the drug moiety. This specific structure is required because a goal of Medford""s work is to maintain the accessability of the xe2x80x94C(S)xe2x80x94Sxe2x80x94 moiety as a reactive species.
It is well recognized that aspirin and other NSAIDs exert their pharmacological effects through the inhibition of cyclooxygenase (COX) enzymes, thereby blocking prostaglandin synthesis (see, for example, J. R. Van in Nature, 231:232-235 (1971)). There are two types of COX enzymes, namely COX-1 and COX-2. COX-1 is expressed constitutively in many tissues, including the stomach, kidney, and platelets, whereas COX-2 is expressed only at the site of inflammation (see, for example, S. Kargan et al. in Gastroenterol., 111:445-454 (1996)). The prostagladins derived from COX-1 are responsible for many of the physiological effects, including maintenance of gastric mucosal integrity.
Many attempts have been made to develop NSAIDs that only inhibit COX-2, without impacting the activity of COX-1 (see, for example, J. A. Mitchell et al., in Proc. Natl. Acad. Sci. USA 90:11693-11697 (1993); and E. A. Meade et al., in J. Biol. Chem., 268:6610-6614 (1993)). There are at least two NSAIDs presently on the market (i.e., nabumetone and etodolac) that show marked selectivity for COX-2 (see, for example, E. A. Meade, supra.; and K. Glaser et al., in Eur. J. Pharmacol. 281:107-111 (1995)). These drugs appear to have reduced gastrointestinal toxicity relative to other NSAIDs on the market.
On the basis of encouraging clinical as well as experimental data, the development of highly selective COX-2 inhibitors appears to be a sound strategy to develop a new generation of anti-inflammatory drugs. However, the physiological functions of COX-1 and COX-2 are not always well defined. Thus, there is a possibility that prostagladins produced as a result of COX-1 expression may also contribute to inflammation, pain and fever. On the other hand, prostagladins produced by COX-2 have been shown to play important physiological functions, including the initiation and maintenance of labor and in the regulation of bone resorption (see, for example, D. M. Slater et al., in Am. J. Obstet. Gynecol., 172:77-82 (1995); and Y. Onoe et al., in J. Immunol. 156:758-764 (1996)), thus inhibition of this pathway may not always be beneficial. Considering these points, highly selective COX-2 inhibitors may produce additional side effects above and beyond those observed with standard NSAIDs, therefore such inhibitors may not be highly desirable.
Accordingly, there is still a need in the art for modified forms of NSAIDs, and other pharmacologically active agents, which cause a reduced incidence of side-effects, relative to the incidence of side-effects caused by such pharmacologically active agents as aspirin, ibuprofen, and the like.
In accordance with the present invention, there are provided conjugates of physiologically compatible dithiocarbamates (DC) and pharmacologically active agents (e.g., NSAIDs). Invention conjugates (e.g., DC-NSAIDs) provide a new class of pharmacologically active agents (e.g., anti-inflammatory agents) which cause a much lower incidence of side-effects due to the protective effects imparted by modifying the pharmacologically active agents as described herein.
There are a number of advantages of conjugates according to the invention (e.g., DC-NSAID), including:
(i) reduced topical irritant effects of NSAIDs, and
(ii) enhanced tissue delivery of both drugs as a result of a decrease in net charges on the molecule, particularly for acidic NSAIDs such as naproxen, aspirin, diclofenac and ibuprofen, thereby reducing the quantity of material which must be delivered to achieve an effective dosage.
In accordance with the present invention, cleavage of the novel bio-cleavable conjugates described herein releases the active pharmaceutical agent. In contrast to the prior art, however (see, for example, Medford et al., referred to above), no free dithiocarbamate is released upon such cleavage. In the event the dithiocarbamate linkage is cleaved, a thiocarbonylcarboxy moiety (xe2x80x94C(S)xe2x80x94Oxe2x80x94) will be generated instead of the dithiocarbonyl moiety (xe2x80x94C(S)xe2x80x94Sxe2x80x94) required for a dithiocarbamate functionality. Thus, the means selected for linkage of a pharmacologically active agent to a dithiocarbamate has a dramatic effect on the species released in situ.